tbuckley/cabot-search huggingface dataset:
5616493 MACHINE LEARNING TO IDENTIFY CHILDREN WITH SICKLE CELL DISEASE AT VERY LOW HIGH RISK OF ABNORMAL OR CONDITIONAL TRANSCRANIAL DOPPLER SCREENING.
Authors: K.W.M. McKinley, R.N. Nickel, J.M.C. Chamberlain, A.C. Campbell, J.K.H. Hyer, M.G.L. Linguraru
Journal: HemaSphere (2023)

Background: Annual Transcranial doppler (TCD) screening is an important strategy to mitigate the risk of stroke in children with sickle cell anemia (SCA). While an abnormal TCD is strongly associated with increased chance of stroke, the risk factors for an abnormal doppler study are not well understood. Identifying children at very low risk could help to ensure appropriate focus on screening children at the highest risk. Machine learning presents an opportunity to develop a risk prediction model, incorporating complex interactions between variables. Aim: Identify potential predictive features for normal TCD screens by applying machine learning algorithms to clinical data collected for a multi-site collaboration, Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE).1 Methods: We analyzed clinical data collected for the 28-site DISPLACE study, which included 5116 patients in whom a TCD was indicated.1 For the current study, we included patients, aged 2-16 years, who had both hemoglobin and TCD results reported in the same year between 2012-2016 (N = 2234); after excluding patients who had prior studies with abnormal or conditional results, our analysis dataset included 22 predictive features (maximum missingness: 25.7%) for 1825 children (N = 30 with abnormal, N = 122 with conditional results). We applied traditional logistic regression, logistic regression with LASSO, and tree-based classifiers to 19 features including historical, biometric, vital sign, and laboratory data, to predict the risk of abnormal or conditional TCD. Results: In univariate logistic regression models, all 19 features had a statistically significant relationship with TCD outcome. Eight features (age, hemoglobin, heart rate, systolic blood pressure, oxygen saturation, weight, mean corpuscular volume, and percent reticulocytes) were shown to be of consistently high importance across different machine learning models. Conclusion: Next steps include development of ensemble models to optimize predictive performance and internal validation on our hold-out test set. Machine learning shows promise for identifying low risk children with SCD who may not require annual TCD screening, such that TCD resources can be appropriately directed to higher risk children to mitigate the risk of stroke.Reference 1. Kanter et al, J Pediatr Hematol Oncol 2021; 43:e1062-8
TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms
Authors: Mithun Vinod Shah, Elizabeth Ngoc Hoa Tran, Syed Shah, Rakchha Chhetri, Anmol Baranwal, Dariusz Ladon, Carl Shultz, Aref Al-Kali, Anna L. Brown, Dong Chen, Hamish S. Scott, Patricia Greipp, Daniel Thomas, Hassan B. Alkhateeb, Deepak Singhal, Naseema Gangat, Sharad Kumar, Mrinal M. Patnaik, Christopher N. Hahn, Chung Hoow Kok, Ayalew Tefferi, Devendra K. Hiwase
Journal: Blood Cancer Journal (2023)

Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53
5613374 ASSOCIATION BETWEEN GENOTYPE AND DISEASE COMPLICATIONS IN EGYPTIAN PATIENTS WITH BETA THALASSEMIA
Authors: T.H. Hassan, M. Zakaria, M. Fathy, M. Arafa, S. El Gebaly, A. Emam, A. Abdel Wahab, M. Shehab, H. Salah, M. Malek, K. El Gerby
Journal: HemaSphere (2023)

Background: In beta thalassemia, the degree of globin chain imbalance is determined by the nature of the mutation of the β-gene. β° refers to the complete absence of production of β-globin on the affected allele. β+ refers to alleles with some residual production of β-globin. The homozygous state results in severe anemia that necessitates regular blood transfusion. On the other hand, frequent blood transfusion can lead to iron overload resulting in progressive dysfunction of the heart, Liver as well as multiple endocrinopathies. Aim: We aimed to evaluate the impact of genotype on the development of disease complications in patients with β thalassemia. Methods: A Cross sectional study was carried on 73 patients with beta thalassemia. Genotyping was determined by DNA sequencing technique. Routine investigations as well as MRI liver and heart were performed to assess iron overload. Results: We found that β+β+ was the most common genotype in our patients followed by β°β° and β°β+. Mean Liver iron content (LIC) was significantly higher in β°β° compared to β°β+ and β+β+ genotypes and mean cardiac T2* was significantly lower in β°β° compared to β°β+ and β+β+ genotypes. Hepatic complications, hepatitis C, cardiac complications and some endocrinopathies were significantly higher in patients with β°β° genotype compared to other genotypes which explain the role of the underlying genetic defect in thalassemia patients in development of disease complications. Conclusion: Clinical severity of thalassemia and development of such complications can be influenced by the type of β-thalassemia mutation and genotype. References 1. Skordis et al, Eur J Haematol. 2006;77:150. 2. Galanello and Cao, Ann N Y Acad Sci. 1998;850:325. 3. Al-Akhras et al, Biomed Rep. 2016;4:728.
Reaching Populations to Address Disparities in Cancer Care Delivery: Results From a Six-Site Initiative
Authors: Noël Arring, Christopher R. Friese, Bidisha Ghosh, Marita Titler, Heidi Hamann, Sanja Percac-Lima, Adrian Sandra Dobs, Michelle J. Naughton, Pooja Mishra, Melissa A. Simon, Bingxin Chen, Electra D. Paskett, Robert J. Ploutz-Snyder, Martha Quinn, Debra L. Barton
Journal: Journal of the National Comprehensive Cancer Network (2023)

Large segments of the US population do not receive quality cancer care due to pervasive and systemic inequities, which can increase morbidity and mortality. Multicomponent, multilevel interventions can address inequities and improve care, but only if they reach communities with suboptimal access. Intervention studies often underenroll individuals from historically excluded groups.The Alliance to Advance Patient-Centered Cancer Care includes 6 grantees across the United States who implemented unique multicomponent, multilevel intervention programs with common goals of reducing disparities, increasing engagement, and improving the quality of care for targeted populations. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework informed the evaluation efforts across sites. Each Alliance site identified their intended populations, which included underrepresented minorities (eg, Black and Latinx persons), individuals who prefer a language other than English, and rural residents. We evaluated the demographic characteristics of participants to determine program reach.Between 2018 and 2020, a total of 2,390 of 5,309 potentially eligible participants were enrolled across the 6 sites. The proportion of enrolled individuals with selected characteristics included 38% (n=908) Black adults, 24% (n=574) Latinx adults, 19% (n=454) preferring a language other than English, and 30% (n=717) rural residents. The proportion of those enrolled who were the intended population was commensurate to the proportion with desired characteristics in those identified as potentially eligible.The grantees met or exceeded enrollments from their intended populations who have been underserved by quality cancer care into patient-centered intervention programs. Intentional application of recruitment/engagement strategies is needed to reach individuals from historically underserved communities.
5613401 SICKLE CELL DISEASE GENOMICS OF AFRICA (SICKLEGENAFRICA) NETWORK: QUALITATIVE INTERVIEW FINDINGS ON REASONS FOR REFUSAL OF BROAD CONSENT
Authors: J.A. Osae-Larbi, R. Attah, P. Opoku, T.A. Adeyemo, N. Galadanci, O. Nnodu, J. Mgaya, K.A. Anie, S.F. Ofori-Acquah
Journal: HemaSphere (2023)

Background: Sickle Cell Disease Genomics of Africa (SickleGenAfrica) Network is a collaborative project to examine the overarching premise that genetic variation affects the body’s defence against intravascular haemolysis and the development of organ damage in sickle cell disease. In addition, SickleGenAfrica employs community engagement to address fundamental ethical issues relating to genomics research, and this study focussed on broad consent incorporated in the process of informed consent. Objectives: To identify the reasons why some SickleGenAfrica participants refused to provide broad consent for future use of their biological samples and information for other genomics research. Methods: Qualitative research using one-on-one telephone interviews Setting: SickleGenAfrica study sites in Nigeria and Tanzania Participants: SickleGenAfrica site investigators based in Abuja, Kano, Lagos and Dar es Salaam study sites Analysis: Inductive thematic analysis Results: Overall, findings from the SickleGenAfrica project revealed that broad consent for future genomics research was obtained from all participants at two study sites in Accra and Kumasi (Ghana). Nonetheless, a small number of participants at four study sites in Nigeria and Tanzania refused broad consent stating reasons including concerns about confidentiality, unavailable updated information for future research, and lack of immediate benefits from genomic research. In addition, psychosocial factors such as gender differences, family dynamics with autonomous decision-making, and beliefs about possible spiritual uses of blood samples. Furthermore, insufficient information and limited understanding about genomics research emerged as reasons for refusal of broad consent. Conclusions: Continuous education to address ethical issues in genomics research, culturally sensitive psychosocial interventions for participants, and recommendations from beneficiaries of genomics research are required to help obtain broad consent in Africa. References 1. Anie et al, BMJ Open 2021; 11:7 2. Ofori-Acquah, The Lancet Global Health 2020; 8:10
5613251 RAPIDLY PROGRESSING MOYAMOYA SYNDROME IN SICKLE CELL DISEASE -- CASE REPORT
Authors: J.L. Joana, A.V. Ana, C.E. Carlos, T.F. Teresa
Journal: HemaSphere (2023)

Introduction: Moyamoya syndrome (MMS) is an uncommon cerebrovascular complication of Sickle Cell Disease (SCD) characterized by progressive narrowing of large intracranial vessels and development of small-vessel collaterals. This association leads to a significant risk of ischemic stroke and poor neurologic outcomes. Case description: We present a case of a 5-year-old female child, with irregular follow-up at Pediatric Hematology Consultation due to Sickle Cell Disease, who presented to our hospital with a first ischemic stroke. The magnetic resonance angiography (MRA) showed narrowing of the terminal portions of the right internal carotid artery, the proximal segments of the right middle and anterior cerebral arteries and the A1 segment of left anterior cerebral artery, with multiple collaterals, aspects highly suggestive of MMS. She initiated hydroxycarbamide, acetylsalicylic acid and chronic red blood cell exchange (RBCX) aiming HbS<30% and 3 months later she presented with a new transient ischemic stroke. She was submitted to right encephaloduroarteriosynangiosis (EDAS) and was stable, without new ischemic events, until 1 year later when she presented with a new transient ischemic stroke of the left cerebral territory. Since then, she had multiple recurrent ischemic events with total recovery of neurologic deficits. MRA and Computed tomography (CT) showed multiple diffuse areas of cerebral infarction and bilateral severe segmental stenosis of internal carotid, middle and anterior cerebral arteries. Discussion/Conclusion: The literature review suggests that early detection and surgical revascularization in addition to RBCX could significantly reduce stroke recurrence and improve neurocognitive outcome. However, in this case, despite the recommended treatment, it was not possible to prevent the rapid progression of MMS, revealing the complexity of the approach to these patients. References 1. Valentine Brousse,Manoelle Kossorotoff and Mariane de Montalembert,British Journal of Haematology, 2015,170,615–625 2. Danielle Terrell et al, World Neurosurgery Volume 137, May 2020, pag 52-70
5610178 SURVIVAL AND COMPLICATIONS IN PATIENTS WITH HEMOGLOBINOPATHIES: THE EXPERIENCE OF A SINGLE DEPARTMENT OF THALASSEMIA AND SICKLE DISEASE
Authors: X.A. Xydaki, K.A. Kotsiafti, M.K. Manganas, P.A. Paraskeva, P.D. Patsourakos, A.K. Aggeli, S.C. Savvidis, K.I. Koskinas, D.S. Delicou
Journal: HemaSphere (2023)

Background: New medicines and doctors’ expertise have increased hemoglobinopathies patients’ survival from 35 to 60 years in the last few decades. This report presents the underlying causes of death in a thalassemia and sickle cell disease unit during the past decade and examines potential risk factors. All causes of death were reported and correlated with comorbidities that may have contributed to this outcome. Methods: The records of 32 patients (17 women/15 men) who died in the Thalassemia and Sickle Cell Disease Unit in the last 10 years were reviewed: 11 had thalassemia, 10 had thalassemia/sickle cell disease, 9 had NTD, and 2 had sickle cell disease. Patients died at a median age of 42 years (range 29-71). Results: Heart failure (8, 25%), HCC (72%), and sepsis (6, 19%) were the leading reasons of mortality.The immediately subsequent causes of death that were recorded were as follows: sudden death three cases (9.5%), liver failure three cases (9.5%), brain aneurysm one case (1%), motor neuron disease one case (1%), and an car accident one time respectively. Using the Pearson Correlation Coefficient, a positive correlation (r:0.8) was found between deaths from heart failure, HCC, and liver failure in patients with a high iron load, as well as a moderate correlation (r:0.3) of HCV infection in patients who died of HCC and liver failure, with no correlation in the remaining deaths. Similarly, no death was associated with splenectomy or the number of transfusions. Conclusions: Despite improvements in better treatment options, heart failure and HCC caused by iron overload continue to be major causes of morbidity and mortality in people with hemoglobinopathies.References 1. Ladis, Vassilis, et al. “Longitudinal study of survival and causes of death in patients with thalassemia major in Greece.” Annals of the New York Academy of Sciences 1054.1 (2005): 445-450. 2. Elmariah, Hany, et al. “Factors associated with survival in a contemporary adult sickle cell disease cohort.” American journal of hematology 89.5 (2014): 530-535.
5610480 TRANSFORMATION OF THALASSAEMIA GENETIC TESTING BY THE IMPLEMENTATION OF NGS-BASED THALASSEMIA ASSAY
Authors: T. Papasavva, G. Christopoulos, M. Petrou, X. Feleki, E. Karitzi, S. Byrou, C. Haughey, B. Vanherberghen, A. Ahlford, M. Kleanthous
Journal: HemaSphere (2023)

Background: The haemoglobinopathies, are the most common monogenic diseases worldwide, and have been recognized as a growing global health challenge. Thalassemia is a serious health problem in Cyprus where 12 % of the population are carriers of beta-thalassaemia and about 19% are carriers of alpha-thalassaemia[1]. Because of the high incidence of the disease and the heavy impact on the health care system, the Cyprus National Prevention Programme was initiated and is successfully running since 1978. The traditional strategy for thalassaemia molecular diagnosis was designed either to identify only the most common mutations, or to target the main causing genes of thalassaemia, HBA, and HBB by conventional molecular techniques such as PCR, Real-Time PCR, MLPA, Sanger sequencing, and Mini sequencing. The complex analysis with the use of multiple different techniques to obtain a result, can cause prolonged turn-around times and costly processes and may even not be conclusive. Aim: The aim is to replace the laborious conventional molecular testing with a comprehensive analysis of the thalassaemias by the establishment of an NGS-based test for the simultaneous genetic analysis of all variants on both HBA and HBB gene clusters. Methods: A commercial CE-IVD NGS Thalassemia kit, that detects all sequence variants in HBA1, HBA2, and HBB in a single run was evaluated. The assay detects SNVs, and Indels and also uses two independent methods in parallel to detect CNVs. For the initial evaluation, 25 DNA samples with known genotypes, previously characterised in our lab, were used. For the validation study, 100 DNA samples were analysed using the NGS Thalassemia kit in parallel with the conventional molecular methods. The results obtained were assessed and compared. Results: The initial evaluation of the NGS thalassemia assay demonstrated the strength of the assay to accurately detect all variations in the analysed genes. Moreover, the assay also detected variations that were not previously identifiable by our conventional multi-method strategy, Thus, we demonstrated the ability of the assay for complete analysis of thalassaemia. The assay was successfully validated: the results obtained by the NGS assay were in complete concordance with results from parallel analysis by our standard strategy. Hence, the NGS Thalassemia kit was successfully implemented in our daily routine practice. Summary/conclusion: The implementation of the NGS Thalassemia kit allows for comprehensive analysis for the haemoglobinopathies in a single run. It is very efficient compared to our traditional previously conducted thalassemia testing, yielding results of unprecedented quality, as well as saving time on three levels - for the physician, for the lab, and most importantly for the patient. Reference 1. Kountouris, P., et al, Scientific reports, 2016.6: p. 26371.
Using less annotation workload to establish a pathological auxiliary diagnosis system for gastric cancer
Authors: Junlin Lan, Musheng Chen, Jianchao Wang, Min Du, Zhida Wu, Hejun Zhang, Yuyang Xue, Tao Wang, Lifan Chen, Chaohui Xu, Zixin Han, Ziwei Hu, Yuanbo Zhou, Xiaogen Zhou, Tong Tong, Gang Chen
Journal: Cell Reports Medicine (2023)

Pathological diagnosis of gastric cancer requires pathologists to have extensive clinical experience. To help pathologists improve diagnostic accuracy and efficiency, we collected 1,514 cases of stomach H&E-stained specimens with complete diagnostic information to establish a pathological auxiliary diagnosis system based on deep learning. At the slide level, our system achieves a specificity of 0.8878 while maintaining a high sensitivity close to 1.0 on 269 biopsy specimens (147 malignancies) and 163 surgical specimens (80 malignancies). The classified accuracy of our system is 0.9034 at the slide level for 352 biopsy specimens (201 malignancies) from 50 medical centers. With the help of our system, the pathologists' average false-negative rate and average false-positive rate on 100 biopsy specimens (50 malignancies) are reduced to 1/5 and 1/2 of the original rates, respectively. At the same time, the average uncertainty rate and the average diagnosis time are reduced by approximately 22% and 20%, respectively.
Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia
Authors: Christian Rausch, Maja Rothenberg-Thurley, Annika Dufour, Stephanie Schneider, Hanna Gittinger, Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard J. Woermann, Wolfgang Hiddemann, Jan Braess, Michael von Bergwelt-Baildon, Karsten Spiekermann, Tobias Herold, Klaus H. Metzeler
Journal: Leukemia (2023)

Abstract The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18–86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients ( n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel’s C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53 -mutated patients with complex karyotypes as “very adverse”. In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.
Whole-genome sequencing identifies novel predictors for hematopoietic cell transplant outcomes for patients with myelodysplastic syndrome: a CIBMTR study
Authors: Tao Zhang, Paul Auer, Jing Dong, Corey Cutler, Amy E. Dezern, Shahinaz M. Gadalla, H. Joachim Deeg, Aziz Nazha, Karen-Sue Carlson, Stephen Spellman, Yung-Tsi Bolon, Wael Saber
Journal: Journal of Hematology & Oncology (2023)

Recurrent mutations in TP53, RAS pathway and JAK2 genes were shown to be highly prognostic of allogeneic hematopoietic cell transplant (alloHCT) outcomes in myelodysplastic syndromes (MDS). However, a significant proportion of MDS patients has no such mutations. Whole-genome sequencing (WGS) empowers the discovery of novel prognostic genetic alterations. We conducted WGS on pre-alloHCT whole-blood samples from 494 MDS patients. To nominate genomic candidates and subgroups that are associated with overall survival, we ran genome-wide association tests via gene-based, sliding window and cluster-based multivariate proportional hazard models. We used a random survival forest (RSF) model with build-in cross-validation to develop a prognostic model from identified genomic candidates and subgroups, patient-, disease- and HCT-related clinical factors. Twelve novel regions and three molecular signatures were identified with significant associations to overall survival. Mutations in two novel genes, CHD1 and DDX11, demonstrated a negative impact on survival in AML/MDS and lymphoid cancer data from the Cancer Genome Atlas (TCGA). From unsupervised clustering of recurrent genomic alterations, genomic subgroup with TP53/del5q is characterized with the significant association to inferior overall survival and replicated by an independent dataset. From supervised clustering of all genomic variants, more molecular signatures related to myeloid malignancies are characterized from supervised clustering, including Fc-receptor FCGRs, catenin complex CDHs and B-cell receptor regulators MTUS2/RFTN1. The RSF model with genomic candidates and subgroups, and clinical variables achieved superior performance compared to models that included only clinical variables.